1. Field of the Invention
This invention pertains to novel vanilloid receptor (VR) related nucleic acids and polypeptides. In particular, the invention relates to proteins that are homologous to known VRs, nucleic acids encoding such proteins, identification of trkA+ pain-specific genes, and the use of these genes and polypeptides in methods of diagnosing pain, methods of identifying compounds useful in treating pain and methods of treating pain.
2. Background
Pain has been defined as the sensory experience perceived by nerve tissue distinct from sensations of touch, pressure, heat and cold. Individuals suffering from pain typically describe it by such terms as bright, dull, aching, pricking, cutting, burning, etc. This range of sensations, as well as the variation in perception of pain by different individuals, makes a precise definition of pain difficult. Pain as suffering, however, is generally considered to include both the original sensation and the reaction to that sensation. Where pain results from the stimulation of nociceptive receptors and transmitted over intact neural pathways, this is termed nociceptive pain. Alternatively, pain may be caused by damage to neural structures, often manifesting itself as neural supersensitivity, and is referred to as neuropathic pain.
Neuropathic pain is a particular type of pain that has a complex and variable etiology. It is generally a chronic condition attributable to complete or partial transection of a nerve or trauma to a nerve plexus or soft tissue. This condition is characterized by hyperesthesia (enhanced sensitivity to a natural stimulus), hyperalgesia (abnormal sensitivity to pain), allodynia (widespread tenderness, characterized by hypersensitivity to tactile stimuli) and/or spontaneous burning pain. In humans, neuropathic pain tends to be chronic and debilitating, and occurs during conditions such as trigeminal neuralgia, diabetic neuropathy, post-herpetic neuralgia, late-stage cancer, amputation or physical nerve damage.
Most drugs including conventional opioids and antidepressants are not practical against chronic pain such as neuropathic pain, either because they are not effective or have serious side effects. For these reasons, alternate therapies for the management of chronic or neuropathic pain are widely sought.
Stimuli such as heat, cold, stretch, and pressure are detected by specialized sensory neurons within the Dorsal Root Ganglia (DRG). These neurons fire action potentials in response to these mechanical and thermal stimuli, although the molecular mechanism for such detection is not known. Recently, two channels, vanilloid receptor 1 (VR1) and vanilloid receptor-like protein 1 (VRL1), have been isolated from DRG that respond to different thresholds of high heat, and hence act as pain receptors. These channels belong to a family of TRP channels that in C. elegans and D. melanogaster are involved in mechano- and osmoregulation.
The VR1 is a calcium channel with six transmembrane domains and a putative pore domain. The channel can be activated by many distinct reagents, including heat, low pH (high proton concentration is present during injury and inflammation), and capsaicin (the active ingredient in hot chili peppers). The knockout of VR1 in mice has demonstrated that this channel plays a role in pain propagation; however, since the phenotype is rather subtle, it also implies that VR1 is not the sole receptor for high heat and pain. To date, one other homologue of VR1 is known in mammals—the VRL1. VRL1 is structurally very similar to VR1, but is expressed on DRG neurons that are not involved in pain reception (in contrast to VR1).
The somatic sensory neurons detect external stimuli such as heat, cold and noxious stimuli through the activation of thermal and mechanical receptors/channels. The VR family represents the first example of molecules expressed within the DRG that have such activation capabilities. Since these molecules are relatively specific to sensory neurons (for example, VR1 knockout mice do not have phenotypes outside of pain perception), they represent highly promising targets for developing drugs against pain or other thermal noxious stimuli. VR1 knockout mice have demonstrated that other molecules have to be involved in pain perception. However, despite the large amount of interest generated in the scientific community concerning this class of receptors, so far, no other receptors of this class have been identified.
In view of the role of the VR members in pain perception, the identification of new members of VR would allow the development of therapeutic candidates specifically designed to block these new TRP channels, which would enable the treatment of various disorders associated with chronic pain. In addition, the identification of new VR members would permit the screening of various drugs to identify those compounds suitable for further, in-depth studies of therapeutic applications.